There are over 80 different autoimmune diseases that are debilitating against which currently there is no cure. Thus, patients resort to complementary and alternative medicine (CAM) to find relief from pain and inflammation. Multiple Sclerosis (MS) is one such autoimmune disease that affects ~350,000-500,000 people in the US. It is a chronic disease characterized by inflammation in the central nervous system that results in neuron demyelination leading to paralysis. Dietary indoles including indole-3-carbinol (I3C) found in cruciferous vegetables such as cauliflower, cabbage and Brussels sprouts, as well as its derivative, diindolylmethane (DIM) have also been known for their health benefits and for their anti-cancer properties. Interestingly, these compounds can bind to the aryl hydrocarbon receptor (AhR), which is well characterized as a transcription factor that regulates xenobiotic metabolism. Also, recent studies suggested that AhR may also regulate certain important immune functions such as T cell differentiation. We have made an exciting observation that dietary indoles such as DIM can completely suppress the clinical disease in an experimental model of MS known as Experimental Autoimmune Encephalomyelitis (EAE). In the current study, we will test the central hypothesis that treatment with these naturally- occurring indoles is effective against induction and progression of EAE through a central pathway of activation of AhR, leading to suppression of proinflammatory Th1/Th17cells and induction of T regs/Th2 cells via epigenetic regulatory mechanisms such as DNA methylation and miRNA dysregulation that block neuroinflammation. To this end, we will test the following aims: In aim 1, we will examine whether treatment with indoles such as I3C or DIM leads to decreased neuroinflammation by downregulation of Th1 and Th17 cell responses against myelin antigens and upregulation of Th2 and FoxP3+ Tregs. We will test whether activation of AhR by these indoles leads to dysregulation in the Th/Treg cell responses using AhR knock out (KO) mice. In aim 2, we will test the central hypothesis that indoles facilitate Th17 to Treg switch in EAE mice by DNA hypomethylation of Foxp3 gene promoter while silencing the Th17 activity by hypermethylation of IL-17 promoters. Lastly, in aim 3, we will test the hypothesis that administration of these indoles triggers dysregulation in the expression of microRNA-466i and microRNA-325 that leads to increased polarization of Tregs and decreased differentiation of T17 cells. The current study investigates the mechanism of action of plant-derived indoles used as dietary supplements, specifically addressing the role of AhR activation in the regulation of inflammation. These studies should provide novel insights into the basic mechanisms through which plant indoles exhibit anti- inflammatory properties so that they can be used against a wide range of autoimmune and inflammatory diseases.